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DOI: 10.1055/s-0031-1289524
New Reactions Exploring the Chemical Spaces of the Aldol Addition of Active Methylene Compounds
Dedicated to professor Arrigo Scettri on the occasion of his 65th birthday
Publication History
Publication Date:
03 January 2012 (online)
Biographical Sketches
Abstract
During research planning and the development of ideas, organic chemists intuitively work on the chemical space, even if they are often unaware of the nature and the extent of chemical space of organic reactions, in which they are moving. The exploration and the rational analysis of new chemical spaces originating from new tandem and multicomponent aldol additions of active methylene compounds can lead to the development of new efficient and environmentally friendly methodologies and to the synthesis of new libraries of highly functionalised compounds.
1 Introduction
2 Chemical Space of the Aldol Addition of Active Methylene Compounds
3 One-Pot Tandem Aldol Addition-Cyclization Reactions
4 Analysis of Chemical Spaces
Key words
aldol addition - active methylene compounds - tandem aldol addition-cyclization - multicomponent reactions
1 Introduction
Chemical space is so enormous that it is hard to explore. This is a problem for medicinal chemists and chemical biologists who seek new molecules for their biological targets. Current tools, often little more than spreadsheets, display only a few molecules at a time, and typically fail to capture the relationships between molecules. [¹] The total number of possible small organic molecules that populate ‘chemical space’ has been estimated to exceed 1060 - an amount so vast when compared to the number of molecules we have made, [²] or indeed could ever hope to make, that it might as well be infinite. So, it is not surprising that our exploration of chemical space of organic reactions has so far been extremely limited. [³] In fact, most of the effort of organic chemists is directed towards the discovery and development of new methodologies. The goal of these methodological studies is usually a single new reaction or a new application of a known reaction, using different substrates, catalysts, reagents or conditions. A single reaction is usually tested several times on model substrates that belong to the same class and that differ in their substitution pattern. Starting materials are usually commercially or readily available. However, in the search of new methodologies very little effort is devoted to studying the reactivity of the libraries of the obtained new products. This search can be the beginning of the development of new original methodologies and the beginning of the exploration of new chemical spaces. Sets of new chemical infinite universes can derive from the development of a single methodology! Consequently the number of new chemical reactions can be considered infinite! However, the importance of a specific reaction may be judged on its ability to deliver ‘interesting products’ with high yield, chemo-, regio-, stereo-, or enantioselectivity. Further requirements may include generality over a wide range of starting materials as well as productivity aiming at more diverse and complex products or a green-chemistry approach. An ‘ideal’ organic reaction would fulfil at least one of these criteria. Further important questions are related to the definition of ‘interesting products’, especially if we think about how much effort is devoted to drug design and to empirical or virtual screening of chemical libraries in medicinal chemistry. [4] However, in contrast to target-oriented synthesis (TOS) and medicinal or combinatorial chemistry, which aim to access precise or dense regions of chemistry space, diversity-oriented synthesis (DOS) is directed to the broad analysis of the chemical space populated by small molecules having diverse structures. [5] In analogy to combinatorial chemistry, the goals of DOS include the development of several pathways leading to the efficient (three- to five-step) synthesis, using validated chemical protocols. [5] Nevertheless, the rational analysis of the spaces of chemical reactions is directed toward the development of new synthetic methodologies, exploring all the possible transformations that can result from new reaction products in a divergent way. [6] Simple examples can be particularly useful for the comprehension of these concepts and for the description of the chemical space of organic reactions.
2 Chemical Space of the Aldol Addition of Active Methylene Compounds
Although aldol addition is one of the most important tools in carbon-carbon bond-forming reactions, the aldol addition of readily enolizable active methylene compounds is still an important challenge in organic chemistry. [7] Even though the obtained adducts are valuable intermediates in the total synthesis of natural products, [8] [9] a general approach is not available yet. [¹0] However, aldol addition of 1,3-dicarbonyl compounds to formaldehyde is a well-established reaction for hydroxymethylation. [¹¹] [¹²] Aldol addition of metal enolates of malonates has been successfully achieved with α-alkoxy aldehydes in the presence of ZnCl2. [8] [9] Very recently Mahrwald described a catalyst-free aldol addition of several 1,3-dicarbonyl compounds to activated aldehydes like ethyl glyoxylate in good to high yields. [¹0] Even if this could be considered the most effective procedure ever reported, aromatic aldehydes were completely unreactive while inactivated aliphatic aldehydes were not tested. [¹0] In the past several methods have been tried but even under very mild conditions (i.e., in the presence of weak base or weak acid or in a mixture of them, under proline-organocatalysed conditions etc.), variable mixtures of regioisomers, dehydration products, and aldol adducts have been observed. [¹0] [¹³] The main difficulties can be attributed to the scarce stability of the adducts and to the inadequacy of the current methodologies that favour condensation (Knoevenagel reaction) or the retro-aldol process instead of the aldol reaction. This disappointing situation pointed out the lack of a general access to those aldol adducts. For that reason, several other synthetic methods have been used to isolate those products. [¹4]
Scheme 1 Multicomponent aldol reactions of malonates or β-keto esters
However, in our recent studies we have clearly demonstrated that the success of this challenging aldol addition is mainly related to the in-situ trapping of the unstable aldol adducts [¹5a] [b] [d] or to their intramolecular trapping. [¹5c] According to Scheme [¹] , starting from readily available compounds, large classes of new aldols 3a,b were obtained in good to high yield, exploiting a multicomponent one-pot aldol addition-protection reaction (MCR) of β-keto esters 2a or malonates 2b to a wide range of aromatic, heteroaromatic and even aliphatic aldehydes in the presence of TMSCl and DIPEA. The synthesised adducts 3a,b [¹5a] [b] [d] are only a tiny amount of those possible and predictable by this MCRs using different active methylene compounds. Through the exploration of these chemical spaces, every class of readily enolizable active methylene compounds having general formula: EWG-CH2-EWG′ (like β-keto esters, β-diketones, malonates, imidates, thioesters, β-ketosulfoxides, β-ketosulfones, malononitriles, α-cyano ketones, α-cyano esters, etc.) probably will lead to the development of new methodologies and to the synthesis of novel and useful libraries of highly functionalised molecules (Scheme [²] ). However, as demonstrated by our studies [¹5a] [b] [d] β-keto esters 2a are less reactive than malonates 2b and require different reaction conditions to drive these reactions to completion on a wide range of aldehydes. For this reason, a systematic testing of different classes of active methylene compounds will be particularly important for the rationalization of their reactivity.
Scheme 2 Generic aldol addition of active methylene compounds
The obtained aldol adducts 3a,b present a combination of different functional groups and a variety of substituents (R¹, R² and R³) in a new unique scaffold. Considering the unique complexity of the aldols 3 of Scheme [²] , they can be submitted to a series of reactions to give either known molecules, that have been obtained using different methods (this is a cross-linking of different chemical spaces), or new molecules. In other words, the study of the chemistry of these classes of molecules will lead to the development of new methodologies. In the case of β-keto esters, any chemical arrow of Scheme [³] is potentially a new methodology because the study of the feasibility of the reaction, the search of the best reaction conditions and the scope of every single transformation can give new interesting products and new chemical information. For example, the adducts 3a have been usually obtained with rather low diastereoselectivity. Nevertheless a simple alkylation reaction of the 1.3:1 mixture of diastereomers of 3a (R¹ = Ph, R² = Me, R³ = t-Bu) in the presence of MeI and K2CO3 in DMF (reaction D of Scheme [³] ), gave product 4 in good yield and with high diastereoselectivity (95:5). [¹5d] In this way the application of a known reaction to new products gave the opportunity to develop a new highly diastereoselective alkylation methodology to give new molecules with two contiguous quaternary and tertiary stereocenters, an important goal for synthetic organic chemistry. [¹5d]
Scheme 3 A chemical space considering reactivity of MCRs of β-keto esters and of the obtained aldol adducts 3. Reagents and conditions: A: TMSCl, DIPEA, solvent; B: NaBH4, MeOH, 0 ˚C; C: TBAF, THF, 0 ˚C; D: K2CO3, MeI, DMF, 48 h.
Furthermore the possibility to obtain known molecules in a more convenient way was highlighted by the synthesis of known valuable diols 5 (R¹ = Ph, R² = R³ = Me and R¹ = Ph, R² = Me, R³ = t-Bu), useful intermediates in the synthesis of substituted β-lactams and β-lactones 6. [¹6] These compounds were easily obtained in high yield and in a shorter sequence (reduction and deprotection reactions) [¹5d] than those reported in the literature and without the use of toxic metal reagents. [¹6]
The developed MCRs of Scheme [¹] are not enantioselective. Considering the spaces of chemical reactions, how could the development of asymmetric versions of these methodologies be possible? In which chemical spaces can we seek for solving this important problem? In planning enantioselective versions of these reactions we can exploit known chemical spaces in which the activation of silicon chlorides with chiral Lewis bases [¹7] or the use of chiral chlorosilane reagents [¹8] give high enantioselectivity for several C-C bond-forming reactions. Or otherwise we should develop completely new ideas with the combinations of classic metal- or organocatalysed approaches, considering the problem of the instability of the unprotected aldol adducts.
However, since we have also reported a two-step variant of these reactions, in which we used SiCl4 for the aldol addition, followed by a protection reaction performed on the crude mixture of the unstable aldol adducts with TMSCl (Scheme [4] ), [¹5a] [b] the chiral Lewis base activation of SiCl4 can be a good start to face this challenging problem.
On the basis of these ideas, as demonstrated by preliminary experiments on p-nitrobenzaldehyde (1a) using Denmark’s catalyst (A) as chiral Lewis base [¹7] (Scheme [5] , see note 19 for experimental details), [¹9] we have obtained very promising results (see Scheme [5] ) and further studies, in which different reaction conditions, different substrates or chiral Lewis bases may lead to improved methods. Considering the enormity of the chemical spaces represented by Schemes [²] and [³] , the study of asymmetric versions can lead to new libraries of interesting chiral molecules and we may obtain unexpected results for both diastereo- and enantioselectivity.
Scheme 5
3 One-Pot Tandem Aldol Addition-Cyclization Reactions
In analogy to recent studies reported by Ramström and co-workers about Henry reaction to 2-cyanobenzaldehyde 1b, [²0] another interesting example of the aldol addition of active methylene compounds is related to some tandem addition-cyclization-rearrangement reactions of aldehyde 1b with β-keto esters, malonates and 1,3-diketones. This process efficiently leads to a series of new 3-substituted isoindolinones 8 in high yields (Scheme [6] ). [¹5c] This reaction was possible thanks to the intramolecular trapping of the unstable aldol adducts 7b by irreversible cyclization at the cyano group, followed by a rearrangement reaction due to the relatively acidic α-protons of 3-substituted iminophthalan intermediates. [¹5c] [²0]
It is worth noting that the isoindolinone heterocyclic ring is present in a large number of molecules with important biological properties. [²¹] For this reason many synthetic methods have been developed, even if they often require multistep, inflexible strategies for the construction of the heterocyclic ring. [²¹] In comparison, the method we describe is particularly simple and versatile and can give access to new libraries of compounds with interesting highly functionalised structures. For this reason, according to Scheme [6] , the analysis of the spaces of possible chemical transformations of every highly functionalised isoindolinone 8 can lead to a series of known products or new products.
Scheme 6 Tandem aldol-cyclization-rearrangement reaction and chemical spaces of isoindolinones
For example, compound 9, an intermediate in the asymmetric and non-asymmetric synthesis of dopamine D4 receptor 10, was obtained in a shorter way than that reported in the literature, [²¹a] [b] with a simple decarboxylation reaction of dimethylmalonate derivative 8a. [¹5c]
On the basis of the chemical space depicted in Scheme [6] , other studies are in course to enlarge the scope of isoindolinone synthesis using different and more complex active methylene compounds and to further explore the second reactivity of 8 in the synthesis of valuable compounds. Moreover, in the synthesis of isoindolinones 8 at least one stereogenic center is formed. Since organo-catalytic asymmetric synthesis of these important compounds have not yet been reported, [²¹] how is it possible to plan an asymmetric synthesis of 8 exploring the chemical spaces of organic methodologies? Since in our case isoindolinone formation is promoted by tertiary amines and the stereogenic centers are formed in the last step of the reaction mechanism, which is an intramolecular conjugated addition, [¹5c] [²0] we have taken into account the use of chiral tertiary amines, such as cinchona alkaloids, [²²] and the results will be published in due course.
On the basis of these concepts, an important question is: how is it possible to exploit the tandem entrapping of the unstable aldol adducts for the development of new methodologies? One possibility is related to the exploitation of other cyano-substituted aldehydes 1d [²³] or other functional groups in 2-position with respect to the aldehyde group to give cyclization and entrapping of the unstable aldol adducts according to Schemes [7] and [8] . The method described in Scheme [7] is under investigation and gives interesting results about the synthesis of isobenzofuranones 11 in a very mild one-pot tandem aldol-lactonization reaction of the methyl ester of 2-carboxybenzaldehyde 1c in the presence of K2CO3 at room temperature. [²4] Even if several tandem syntheses are reported for the construction of the isobenzofuranone ring, which is present in a large number of natural products with a wide range of biological applications, it is very important to note that they usually proceed via a different mechanism (Knoevenagel followed by Michael cyclization) and usually employ harsh conditions with the use of strong acids or bases, high reaction temperatures, and metal catalysts. [²5] [²6]
Scheme 7 Tandem aldol-lactonization of di-tert-butyl malonate
Scheme 8 Examples of possible tandem aldol-cyclization reactions of active methylene compounds
Furthermore, the possibility to expand the scope of the tandem addition-cyclization-rearrangement reactions will be explored in the presence of other cyano-substituted aldehydes as depicted in Scheme [8] , a route that could be particularly useful for the discovery of new chemical spaces and new libraries of substituted pyrrolidinones and γ-lactams 12, another important class of valuable compounds with a wide range of biological properties. [²7]
4 Analysis of Chemical Spaces
During research planning and the development of ideas, investigators intuitively work on the chemical space, even if they are often unaware of the nature of chemical space in which they are moving. Often the solution of a specific problem relies on the knowledge and rational analysis of the literature and on the determination of the relationships between similar or contiguous chemical spaces. A rational exploration of the chemical space is a prerogative for chemical biologists and pharmacologists for obtaining new libraries with combinatorial chemistry techniques, while research planning for chemists is often based on intuitive and empirical approaches and is limited to a specific problem. The terminology of chemical space has rarely been adopted by chemists. In analogy to medicinal chemistry, [³] [4] is it possible to use automated approaches in order to determine the chemical space of organic transformations? In principle this could be possible. [6] Virtual screening, with the aid of computer-based methods and databases, can be an important tool for the definition, the exploration, the analysis and description of the chemical space of chemical reactions.
Even though the role of serendipity and intuition will never be replaced by computer-based methods and databases, virtual screening of chemical reactions could be a helpful tool for the discovery of new synthetic methodologies. However, the empirical analysis of chemical spaces of the aldol addition of active methylene compounds can give enormous opportunities to develop new reactions and can be the beginning of successful future developments.
Acknowledgment
The author is grateful to Dr. Antonia Di Mola and Mr Vijaykumar More for discussion. Financial support from the MIUR (FARB 2011) is gratefully acknowledged.
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References and Notes
Organic and inorganic substances registered by CAS have just exceeded 63 million (www.cas.org).
19Experimental procedure for SiCl 4 -mediated aldol reaction (Scheme [5] ). In a flame-dried 2-necked round-bottom flask tert-butyl acetoacetate (0.30 mmol) was added to a solution of DIPEA (0.40 mmol), SiCl4 (1.9 mmol), Denmark’s catalyst (0.04 mmol) and aldehyde (0.20 mmol) in dry CH2Cl2 (1.0 mL) under nitrogen at -20 ˚C. At the end of the reaction the mixture was quenched with saturated aqueous NaHCO3 (5 mL), extracted with 15 × 3 mL CH2Cl2 and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure the crude products 7 were analysed by ¹H NMR and subjected to TMS protection.¹5a Chiral HPLC separation of 3aa was performed with a Chiralpak AD-H column in hexane-isopropanol (98:2), 0.6 mL/min.
23Aldehydes 1c can easily be obtained by commercially available dialkylacetal derivatives.
24Experimental procedure for the synthesis of 3-substituted isobenzofuranone 11a. To a solution of aldehyde (0.31 mmol) in DMF (1 mL) and potassium carbonate (0.62 mmol) di-tert-butyl malonate (0.34 mmol) was added dropwise. The mixture was allowed to stir for 24 h. Then it was diluted with ethyl acetate and washed three times with water. The organic layer was dried over Na2SO4 and evaporated to give an oil which was purified by chromatography on silica gel [hexane-ethyl acetate (9:1 to 7:3)]; yield: 93%.
- 1
Kirkpatrick P.Ellis C. Nature 2004, 432: 823 - 3
Irwin JJ. Nat. Chem. Biol. 2009, 5: 536 - 4
Shoichet BK. Nature 2004, 432: 862 - 5
Burke MD.Schreiber SL. Angew. Chem. Int. Ed. 2004, 43: 46 - 6 A conceptually related approach has
recently been reported for the multidimensional reaction screening
of ortho-alkynyl benzaldehydes with a
variety of catalysts and reaction partners in order to identify
new chemical reactions:
Beeler AB.Su S.Singleton CA.Porco JA. J. Am. Chem. Soc. 2007, 129: 1413 - 7 The failure of a planned aldol addition
of substituted cyclohexane-1,3-dione in the total synthesis of coleophomones
is described here:
Nicolaou KC.Montagnon T.Vassilikogiannakis G.Mathison CJN.
J. Am. Chem. Soc. 2005, 127: 8872 - 8 For aldol additions of malonates
in the total synthesis of epolactaene, see:
Marumoto S.Kogen H.Naruto S. J. Org. Chem. 1998, 63: 2068 - 9a For
aldol additions of malonates in the total synthesis of carbohydrates,
see:
Saba A.Adovasio V.Nardelli M. Tetrahedron: Asymmetry 1992, 3: 1573 - 9b For the preparation of
polyfunctional furanic derivatives from trioses, see:
Sanchez Ballesteros J.McPhee DJ.Hernandez Hernandez F. Rev. Roum. Chem. 1981, 26: 899 - 10 For recent studies about catalyst-free
aldol additions of 1,3-dicarbonyl compounds to activated aldehydes,
see:
Rohra K.Mahrwald R. Adv. Synth. Catal. 2008, 350: 2877 ; and references therein - 11a For
hydroxymethylation of 3-benzoyl-2-oxo-ethylpropionate, see:
Couquelet J.Boyer JB.Coquelet J. Compt. Rend. S. Acad. Sciences, Ser. C: Sciences Chim. 1972, 274: 422 - 11b
Cornforth JW, andHawes JE. inventors; German Patent DE 2336394. For the reaction of acetoacetic ethyl ester in the presence of triethylamine, see: - 11c For the hydroxymethylation
of 2-oxocyclohexane- and 2- oxocyclo-pentanecarboxylic acid esters
in the presence of CaO, see:
Gerdes H.Marschall H.Weyerstahl P. Chem. Ber. 1975, 108: 3448 - 11d
Gyuran JJ. inventors; European Patent EP 350320. For the hydroxymethylation of 2,4-pentanedione in the presence of KOH, see: - 11e For the hydroxy-methylation
of malonates, see:
Guzaev A.Lönnberg H. Synthesis 1997, 1281 - 11f For the hydroxymethylation
of α-methyl-substituted acetoacetic ethyl ester, see:
Akeboshi T.Ohtsuka Y.Sugai T.Ohta H. Tetrahedron 1998, 54: 7387 - 11g For iron-catalyzed hydroxymethylation,
see:
Ogawa C.Kobayashi S. Chem. Lett. 2007, 36: 56 - 11h For aldol addition of
formaldehyde to 1,3-dicarbonyl compounds used in the total syntheses
of natural products, see:
Tsuda Y.Ishiura A.Takamura S.Hosoi S.Isobe K.Mohri K. Chem. Pharm. Bull. 1991, 39: 2797 - 11i
Chan TH.Schwerdtfeger AE. J. Org. Chem. 1991, 56: 3294 - See also some more recent articles:
- 12a For aldol addition of formaldehyde
to activated ketones:
Lecomte V.Bolm C. Adv. Synth. Catal. 2005, 347: 1666 - 12b For enantioselective aldol
addition of formaldehyde in the presence of chiral palladium complexes:
Fukuchi I.Hamashima Y.Sodeoka M. Adv. Synth. Catal. 2007, 349: 509 - 12c For an aldol addition
of aqueous formaldehyde with bicyclic β-keto ester, see:
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References and Notes
Organic and inorganic substances registered by CAS have just exceeded 63 million (www.cas.org).
19Experimental procedure for SiCl 4 -mediated aldol reaction (Scheme [5] ). In a flame-dried 2-necked round-bottom flask tert-butyl acetoacetate (0.30 mmol) was added to a solution of DIPEA (0.40 mmol), SiCl4 (1.9 mmol), Denmark’s catalyst (0.04 mmol) and aldehyde (0.20 mmol) in dry CH2Cl2 (1.0 mL) under nitrogen at -20 ˚C. At the end of the reaction the mixture was quenched with saturated aqueous NaHCO3 (5 mL), extracted with 15 × 3 mL CH2Cl2 and dried over anhydrous Na2SO4. After removing the solvent under reduced pressure the crude products 7 were analysed by ¹H NMR and subjected to TMS protection.¹5a Chiral HPLC separation of 3aa was performed with a Chiralpak AD-H column in hexane-isopropanol (98:2), 0.6 mL/min.
23Aldehydes 1c can easily be obtained by commercially available dialkylacetal derivatives.
24Experimental procedure for the synthesis of 3-substituted isobenzofuranone 11a. To a solution of aldehyde (0.31 mmol) in DMF (1 mL) and potassium carbonate (0.62 mmol) di-tert-butyl malonate (0.34 mmol) was added dropwise. The mixture was allowed to stir for 24 h. Then it was diluted with ethyl acetate and washed three times with water. The organic layer was dried over Na2SO4 and evaporated to give an oil which was purified by chromatography on silica gel [hexane-ethyl acetate (9:1 to 7:3)]; yield: 93%.
Scheme 1 Multicomponent aldol reactions of malonates or β-keto esters
Scheme 2 Generic aldol addition of active methylene compounds
Scheme 3 A chemical space considering reactivity of MCRs of β-keto esters and of the obtained aldol adducts 3. Reagents and conditions: A: TMSCl, DIPEA, solvent; B: NaBH4, MeOH, 0 ˚C; C: TBAF, THF, 0 ˚C; D: K2CO3, MeI, DMF, 48 h.
Scheme 5
Scheme 6 Tandem aldol-cyclization-rearrangement reaction and chemical spaces of isoindolinones
Scheme 7 Tandem aldol-lactonization of di-tert-butyl malonate
Scheme 8 Examples of possible tandem aldol-cyclization reactions of active methylene compounds